Synthesis of hydroxymethyl analogues of mannostatin A and their evaluation as inhibitors of GH38 α-mannosidases

• Published in: New journal of chemistry Vol. 45; no. 3; pp. 13539 - 13548
• Main Authors: Kalník, Martin, Zaji ková, Mária, Kó a, Juraj, Šesták, Sergej, Monco, Ján, Koóš, Miroslav, Bella, Maroš
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 14.08.2021; Royal Society of Chemistry
• Subjects: Chemistry; Chemistry, Multidisciplinary; Crystallography; Inhibitors; Jack beans; Physical Sciences; Quantum mechanics; Regioselectivity; Ribose; Ring opening; Science & Technology; Selectivity; Synthesis; DESIGN; MECHANISM; POTENT GLYCOSIDASE INHIBITORS; SWAINSONINE; BIOLOGICAL EVALUATION; SELECTIVE INHIBITORS; AGENTS; DERIVATIVES; EFFICIENT; GALACTO
• ISSN: 1144-0546; 1369-9261
• DOI: 10.1039/d1nj02351a

A synthetic approach to hydroxymethyl analogues of mannostatin A starting from l -ribose is described. The key step employed in the synthesis of homomannostatin A was ring-opening of aziridine intermediates with sodium methanethiolate in DMF. Regioselectivity of these openings was investigated by quantum mechanics calculations. The synthesised hydroxymethyl analogues of mannostatin A were evaluated as inhibitors of three different GH38 α-mannosidases: the Golgi (GMIIb) and lysosomal (LManII) α-mannosidases from Drosophila melanogaster , and commercial Jack bean α-mannosidase (JBMan) from Canavalia ensiformis . The tested compounds exhibited inhibitory activity against GMIIb with IC 50 values in the range of 3-43 μM resulting in selectivity [IC 50 (LManII)/IC 50 (GMIIb)] similar to mannostatin A. Analogues of mannostatin A were synthesised and evaluated as inhibitors of GH38 α-mannosidases. Different regioselectivity of aziridine opening with sodium methanethiolate was observed and investigated by quantum mechanics calculations.